A genomic deep field view of hypertension
Authors: Pranav S. Garimella, Clea du Toit, Nhu Ngoc Le, Sandosh Padmanabhan
Journal: Kidney International (2022)

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing. Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing. Editor's NoteThe development of genetics has profoundly affected the field of hypertension, the most important global risk factor for cardiovascular disease. In their illuminating review, Garimella, Padmanabhan, and colleagues provide an overview of the genetic architecture of blood pressure control, ranging from ultrarare high-impact variants to common polymorphisms and their use for pharmacogenomics and risk stratification through polygenic risk scores. They describe how these insights improved our understanding of fundamental processes involved in NaCl handling, its hormonal regulation, and the vascular counterpart of blood pressure control. These advances are balanced by the need to bridge the gap between genome-wide association study variants and actionable practice; to better understand the role of structural variants, epigenetics, and gene-environment interactions; and to address the uneven access to clinical genomic or genetic services.Nearly 10 million deaths globally per year are attributable to hypertension, making this the commonest modifiable cardiovascular risk factor in both developed and developing countries.1NCD Risk Factor Collaboration (NCD-RisC)Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants.Lancet. 2017; 389: 37-55Abstract Full Text Full Text PDF PubMed Scopus (1442) Google Scholar,2GBD 2016 Risk Factors CollaboratorsGlobal, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2017; 390: 1345-1422Abstract Full Text Full Text PDF PubMed Scopus (1743) Google Scholar The health burden from hypertension arises from strong, continuous, positive relationships between blood pressure (BP) and coronary artery disease (CAD), heart failure, stroke, myocardial infarction, atrial fibrillation, peripheral artery disease, renal failure, and cognitive impairment.3Lewington S. Clarke R. Qizilbash N. et al.Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (7890) Google Scholar,4Rapsomaniki E. Timmis A. George J. et al.Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people.Lancet. 2014; 383: 1899-1911Abstract Full Text Full Text PDF PubMed Scopus (1055) Google Scholar Hypertension is defined by a threshold at the upper end of the BP distribution at which the benefits of action (i.e., therapeutic intervention) exceed those of inaction.5Evans J.G. Rose G. Hypertension.Br Med Bull. 1971; 27: 37-42Crossref PubMed Scopus (97) Google Scholar This simple yet powerful dichotomization has enabled clinical and public health strategies to reduce the global burden of hypertension6Ettehad D. Emdin C.A. Kiran A. et al.Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.Lancet. 2016; 387: 957-967Abstract Full Text Full Text PDF PubMed Scopus (2053) Google Scholar but belies the underlying complexity of BP regulation and hypertension causation involving the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system.7Padmanabhan S. Dominiczak A.F. Genomics of hypertension: the road to precision medicine.Nat Rev Cardiol. 2021; 18: 235-250Crossref PubMed Scopus (57) Google Scholar Perturbations in any component of this system can arise from behavioral, environmental, or genetic factors or a combination of all, leading to increases or decreases in mean BP. The development of genetics has profoundly affected the field of hypertension, the most important global risk factor for cardiovascular disease. In their illuminating review, Garimella, Padmanabhan, and colleagues provide an overview of the genetic architecture of blood pressure control, ranging from ultrarare high-impact variants to common polymorphisms and their use for pharmacogenomics and risk stratification through polygenic risk scores. They describe how these insights improved our understanding of fundamental processes involved in NaCl handling, its hormonal regulation, and the vascular counterpart of blood pressure control. These advances are balanced by the need to bridge the gap between genome-wide association study variants and actionable practice; to better understand the role of structural variants, epigenetics, and gene-environment interactions; and to address the uneven access to clinical genomic or genetic services. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades. The definitions of key terms are presented in Box 1. This has progressed through 2 phases that harken back to the Platt-Pickering debate8Zanchetti A. Platt versus Pickering: an episode in recent medical history.in: An essay review. 30. Med Hist, 1986: 94-96Google Scholar—an earlier fruitful period of identifying rare variants with large effects through linkage analysis of families with rare hypertension and hypotension syndromes and the more recent (last 15 years) expansion of polygenic discoveries from genome-wide association studies (GWASs) catalyzed by advances in genotyping and sequencing technologies, analytical methods, and large-scale collaborations.9Lifton R.P. Gharavi A.G. Geller D.S. Molecular mechanisms of human hypertension.Cell. 2001; 104: 545-556Abstract Full Text Full Text PDF PubMed Scopus (1381) Google Scholar, 10Pazoki R. Dehghan A. Evangelou E. et al.Genetic predisposition to high blood pressure and lifestyle factors: associations with midlife blood pressure levels and cardiovascular events.Circulation. 2018; 137: 653-661Crossref PubMed Scopus (120) Google Scholar, 11Giri A. Hellwege J.N. Keaton J.M. et al.Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.Nat Genet. 2019; 51: 51-62Crossref PubMed Scopus (215) Google Scholar, 12Surendran P. Feofanova E.V. Lahrouchi N. et al.Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.Nat Genet. 2020; 52: 1314-1332Crossref PubMed Scopus (54) Google Scholar, 13Sakaue S. Kanai M. Tanigawa Y. et al.A cross-population atlas of genetic associations for 220 human phenotypes.Nat Genet. 2021; 53: 1415-1424Crossref PubMed Scopus (197) Google Scholar, 14Backman J.D. Li A.H. Marcketta A. et al.Exome sequencing and analysis of 454,787 UK Biobank participants.Nature. 2021; 599: 628-634Crossref PubMed Scopus (142) Google Scholar Currently, the genetic architecture of hypertension encompasses ∼30 monogenic rare variants and >1500 single nucleotide variants comprising both low-frequency and common variants reflecting the continuous spectrum of risk alleles influencing BP and consequently hypertension. Although monogenic variants implicate causal genes illuminating underpinning mechanisms, the wealth of common variants contrasts with the paucity of success in connecting to causal pathways. The immediate and direct application of GWAS results in clinical practice or translational studies looks unfeasible, and nascent functional studies to follow up GWAS signals require years to generate actionable results. Notwithstanding these, there have been unexpected early wins including expansion of our understanding of the complex causation of hypertension; confirmation and/or refinement of causal estimates bidirectionally between BP, risk factors, and outcomes through Mendelian randomization; understanding opportunities and requirements for risk prediction using polygenic risk scores; and opportunities for precision medicine and drug repurposing.Box 1Definition of key termsLinkage analysis. A powerful tool to detect the chromosomal location of disease genes. It is based on the observation that genes that reside physically close on a chromosome remain linked during meiosis. It attempts to locate a disease-causing gene by identifying genetic markers of known chromosomal location that are co-inherited with the trait of interest. It requires a well-defined trait (phenotype), an extensive pedigree of families usually with multiple generations, and genetic markers and maps.Genome-wide association studies (GWASs). This involves testing hundreds of thousands of common genetic variations across the DNA of large numbers of individuals to find those statistically associated with a specific trait or disease. GWAS results have a range of applications, such as gaining insight into a phenotype's underlying biology, estimating its heritability, calculating genetic correlations, making clinical risk predictions, informing drug development, and inferring potential causal relationships between risk factors and health outcomes.Single-nucleotide polymorphisms (SNPs). They are the most common type of naturally occurring genetic variation among people. Each SNP represents a single base substitution in the human genome with a population frequency of >1%. SNPs occur approximately once in every 1000 nucleotides throughout the genome, which means each individual's genome contains ∼4 to 5 million SNPs.Phenome-wide association studies (PheWAS). This is an unbiased approach to test for associations between a specific single-nucleotide polymorphism (SNP) or a combination of genetic variants across a wide range of phenotypes in large populations. The direction of inference in a PheWAS is from a SNP to multiple phenotypes, whereas in genome-wide association studies it is from one phenotype to multiple SNPs. They are well-suited to facilitate the identification of new associations between SNPs and phenotypes as well as between SNPs and pleiotropy. PheWAS have been proposed to enhance drug development through elucidating mechanisms of action, identifying alternative indications, predicting adverse drug events, and opportunities for drug repurposing.Pleiotropy. A phenomenon whereby a single genetic variant influences ≥2 apparently unrelated phenotypic traits via independent biological pathways, for instance, because of the effects in different tissues or because the effect of the variant on one trait is causally related to variation in another trait.Polygenic risk score (PRS). A single value estimate of an individual's genetic susceptibility to a phenotype, calculated as a sum of the genome-wide genotypes weighted by corresponding genotype effect size estimates derived from genome-wide association study (GWAS) data. Classic genetic risk scores include only a reduced set of single-nucleotide polymorphisms (SNPs) that fulfill a statistical level of significance. In contrast, PRS include millions of SNPs, explicitly modeling the correlation structure between SNPs without identifying a minimal subset of SNPs for prediction. These risk scores have limited predictive accuracy as they cannot confidently predict the clinical outcome of interest with precision at the individual patient level. PRS-based risk stratification could be of potential utility for diseases that already have population-based screening and prevention programs where additional information from PRS can direct screening toward a more restricted group, which could potentially decrease the risks associated with screening the population overall, and lead to cost savings.Mendelian randomization (MR). MR uses genetic variation as a natural experiment to investigate the causal relationships between potentially modifiable risk factors and diseases or phenotypes in observational data. Major limitations of evidence from observational studies include unmeasured confounding and reverse causality. The idea behind MR is that as genotype is randomly allocated at conception and is invariant over the lifetime, they can be used as genetic proxies unaffected by confounding or reverse causation to infer causality. A valid MR study depends on the genetic variant (instrument) fulfilling 3 key assumptions: they associate with the risk factor of interest; they share no common cause with the outcome; and they do not affect the outcome except through the risk factor. Linkage analysis. A powerful tool to detect the chromosomal location of disease genes. It is based on the observation that genes that reside physically close on a chromosome remain linked during meiosis. It attempts to locate a disease-causing gene by identifying genetic markers of known chromosomal location that are co-inherited with the trait of interest. It requires a well-defined trait (phenotype), an extensive pedigree of families usually with multiple generations, and genetic markers and maps. Genome-wide association studies (GWASs). This involves testing hundreds of thousands of common genetic variations across the DNA of large numbers of individuals to find those statistically associated with a specific trait or disease. GWAS results have a range of applications, such as gaining insight into a phenotype's underlying biology, estimating its heritability, calculating genetic correlations, making clinical risk predictions, informing drug development, and inferring potential causal relationships between risk factors and health outcomes. Single-nucleotide polymorphisms (SNPs). They are the most common type of naturally occurring genetic variation among people. Each SNP represents a single base substitution in the human genome with a population frequency of >1%. SNPs occur approximately once in every 1000 nucleotides throughout the genome, which means each individual's genome contains ∼4 to 5 million SNPs. Phenome-wide association studies (PheWAS). This is an unbiased approach to test for associations between a specific single-nucleotide polymorphism (SNP) or a combination of genetic variants across a wide range of phenotypes in large populations. The direction of inference in a PheWAS is from a SNP to multiple phenotypes, whereas in genome-wide association studies it is from one phenotype to multiple SNPs. They are well-suited to facilitate the identification of new associations between SNPs and phenotypes as well as between SNPs and pleiotropy. PheWAS have been proposed to enhance drug development through elucidating mechanisms of action, identifying alternative indications, predicting adverse drug events, and opportunities for drug repurposing. Pleiotropy. A phenomenon whereby a single genetic variant influences ≥2 apparently unrelated phenotypic traits via independent biological pathways, for instance, because of the effects in different tissues or because the effect of the variant on one trait is causally related to variation in another trait. Polygenic risk score (PRS). A single value estimate of an individual's genetic susceptibility to a phenotype, calculated as a sum of the genome-wide genotypes weighted by corresponding genotype effect size estimates derived from genome-wide association study (GWAS) data. Classic genetic risk scores include only a reduced set of single-nucleotide polymorphisms (SNPs) that fulfill a statistical level of significance. In contrast, PRS include millions of SNPs, explicitly modeling the correlation structure between SNPs without identifying a minimal subset of SNPs for prediction. These risk scores have limited predictive accuracy as they cannot confidently predict the clinical outcome of interest with precision at the individual patient level. PRS-based risk stratification could be of potential utility for diseases that already have population-based screening and prevention programs where additional information from PRS can direct screening toward a more restricted group, which could potentially decrease the risks associated with screening the population overall, and lead to cost savings. Mendelian randomization (MR). MR uses genetic variation as a natural experiment to investigate the causal relationships between potentially modifiable risk factors and diseases or phenotypes in observational data. Major limitations of evidence from observational studies include unmeasured confounding and reverse causality. The idea behind MR is that as genotype is randomly allocated at conception and is invariant over the lifetime, they can be used as genetic proxies unaffected by confounding or reverse causation to infer causality. A valid MR study depends on the genetic variant (instrument) fulfilling 3 key assumptions: they associate with the risk factor of interest; they share no common cause with the outcome; and they do not affect the outcome except through the risk factor. A direct relationship between excess Na+ intake and hypertension has been well recognized for a long time and further confirmed by epidemiological studies and clinical trials.15Adrogue H.J. Madias N.E. Sodium and potassium in the pathogenesis of hypertension.N Engl J Med. 2007; 356: 1966-1978Crossref PubMed Scopus (559) Google Scholar This implied that perturbations in physiological pathways that maintain Na+ homeostasis may be the underlying cause of hypertension. A majority of the early monogenic BP syndromes involved mutations in genes in the kidney tubules and adrenal glands with roles in tubular Na+ transport mechanisms, suggesting the importance of Na+ in BP regulation. GWASs have also identified single-nucleotide polymorphisms (SNPs) near genes involved in Na+ pathways with varying levels of functional validation (Figure 1). Gordon syndrome (pseudohypoaldosteronism type II), which is linked to 4 genetic defects involving the WNK1, WNK4, KLHL3, and CUL3 genes,16Mansfield T.A. Simon D.B. Farfel Z. et al.Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.Nat Genet. 1997; 16: 202-205Crossref PubMed Scopus (201) Google Scholar is the only form of monogenic hypertension that manifests as low-renin hypoaldosteronism with hyperkalemia and acidosis.17Louis-Dit-Picard H. Barc J. Trujillano D. et al.KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.Nat Genet. 2012; 44 (S451–S453): 456-460Crossref PubMed Scopus (262) Google Scholar,18Glover M. Ware J.S. Henry A. et al.Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome).Clin Sci (Lond). 2014; 126: 721-726Crossref PubMed Scopus (42) Google Scholar Mutations in these genes result in the lack of inhibition of WNK4 kinase by the protein products kelch-like 3, cullin 3, and with-no-lysine kinase 1 (WNK1), thereby leading to with-no-lysine kinase 4 (WNK4) accumulation and overactivity of the thiazide-sensitive Na+-Cl− cotransporter (NCC), which, in turn, causes hypertension with acidosis and hyperkalemia. Clinically, it is a biochemical and phenotypic "mirror image" of Gitelman syndrome (see below) and treatment is by blocking the Na+-Cl− cotransporter with thiazide diuretics.19Mabillard H. Sayer J.A. The molecular genetics of Gordon syndrome.Genes (Basel). 2019; 10: 986Crossref PubMed Scopus (32) Google Scholar Liddle syndrome is an autosomal dominant low-renin and low-aldosterone hypertension disorder resulting from frameshift mutations in the genes coding the β and γ subunits of the epithelial Na+ channel (encoded by SCNN1B or SCNN1G).20Hansson J.H. Nelson-Williams C. Suzuki H. et al.Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome.Nat Genet. 1995; 11: 76-82Crossref PubMed Scopus (727) Google Scholar,21Hiltunen T.P. Hannila-Handelberg T. Petajaniemi N. et al.Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit.J Hypertens. 2002; 20: 2383-2390Crossref PubMed Scopus (75) Google Scholar Consequently, these regions are unable to bind to the ubiquitin ligase neural precursor cell expressed developmentally down-regulated protein 4-2 (Nedd4-2), resulting in disruption of epithelial Na+ channel internalization and proteasomal degradation with consequent overexpression and increased sodium reabsorption independent of aldosterone.22Abriel H. Loffing J. Rebhun J.F. et al.Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome.J Clin Invest. 1999; 103: 667-673Crossref PubMed Scopus (329) Google Scholar The typical clinical features are suppressed plasma renin and aldosterone levels, hypokalemic metabolic alkalosis, and early-onset hypertension. Blockers of the epithelial Na+ channel—amiloride and triamterene (not aldosterone antagonists)—ameliorate the condition. Like Liddle syndrome, the syndrome of apparent mineralocorticoid excess is also characterized by hypertension, hypokalemia, and metabolic alkalosis but caused by a deficiency of 11β-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene.23Ulick S. Levine L.S. Gunczler P. et al.A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol.J Clin Endocrinol Metab. 1979; 49: 757-764Crossref PubMed Scopus (510) Google Scholar,24Morineau G. Sulmont V. Salomon R. et al.Apparent mineralocorticoid excess: report of six new cases and extensive personal experience.J Am Soc Nephrol. 2006; 17: 3176-3184Crossref PubMed Scopus (82) Google Scholar The primary role of this enzyme is the peripheral metabolism of cortisol to cortisone, thus preventing its binding to the mineralocorticoid receptor. Lack of the enzyme results in unopposed mineralocorticoid activation and Na+ reabsorption.25Ceccato F. Mantero F. Monogenic forms of hypertension.Endocrinol Metab Clin North Am. 2019; 48: 795-810Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Management is with mineralocorticoid receptor antagonists, K+ supplements, and dietary Na+ restriction. Geller syndrome is caused by heterozygous mutation of the mineralocorticoid receptor gene (nuclear receptor subfamily 3 group C member 2, NR3C2),26Geller D.S. Farhi A. Pinkerton N. et al.Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy.Science. 2000; 289: 119-123Crossref PubMed Scopus (554) Google Scholar resulting in increased Na+ reabsorption and hypertension arising from activation of mineralocorticoid receptors by progesterone. This presents as severe hypertension during pregnancy when progesterone levels are increased. Mineralocorticoid receptor antagonists such as spironolactone paradoxically exacerbate hypertension and electrolyte disturbances and are thus contraindicated. This is because the mutation alters the binding parameters of the ligand-binding domain of the mineralocorticoid receptor, increasing its affinity for spironolactone. The causal role of Na+ in hypertension is further bolstered by the identification of mutations that result in Na+ wasting and hypotension. Classic Bartter syndrome types 1 and 2 are disorders of the thick ascending limb of loop of Henle (TAL) resulting from variants in SLC12A1 and KCNJ1 genes with the consequent loss of function of Na+-K+-Cl− cotransporter 2 (NKCC2) and K+ rectifier channel (KCNJ1), respectively (Figure 1).27Konrad M. Nijenhuis T. Ariceta G. et al.Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders.Kidney Int. 2021; 99: 324-335Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Bartter syndrome types 3, 4a, and 4b are specific to the distal convoluted tubule involving the CLCNKB, BSND, and CLCNKA genes, which encode proteins for the Cl− channels ClC-Kb, barttin, and CLC-Ka, respectively. Type 4 exhibits sensorineural hearing loss in addition to hypotension and hypokalemic metabolic alkalosis seen with all Bartter syndromes.28Birkenhager R. Otto E. Schurmann M.J. et al.Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.Nat Genet. 2001; 29: 310-314Crossref PubMed Scopus (435) Google Scholar, 29Janssen A.G. Scholl U. Domeyer C. et al.Disease-causing dysfunctions of barttin in Bartter syndrome type IV.J Am Soc Nephrol. 2009; 20: 145-153Crossref PubMed Scopus (64) Google Scholar, 30Nozu K. Inagaki T. Fu X.J. et al.Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness.J Med Genet. 2008; 45: 182-186Crossref PubMed Scopus (73) Google Scholar Each of these variants is inherited in an autosomal recessive manner, whereas Bartter syndrome type 5 involving the melanoma-associated antigen D2 (MAGED2) gene shows X-linked inheritance and exhibits defects in both the TAL and the distal convoluted tubule.31Laghmani K. Beck B.B. Yang S.S. et al.Polyhydramnios, transient antenatal Bartter's syndrome, and MAGED2 mutations.N Engl J Med. 2016; 374: 1853-1863Crossref PubMed Scopus (119) Google Scholar Gitelman syndrome (familial hypokalemia hypomagnesemia) is the most common inherited tubulopathy (1 in 40,000), and although similar to Bartter syndrome with respect to hypotension and hypokalemic metabolic alkalosis, it is additionally characterized by hypomagnesemia and hypocalciuria. Gitelman syndrome results from biallelic inactivation of the SLC12A3 gene32Blanchard A. Bockenhauer D. Bolignano D. et al.Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 24-33Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar encoding the Na+-Cl− cotransporter expressed in the apical membrane of cells lining the distal convoluted tubule. To date, >350 mutations have been identified, with most patients being compound heterozygous for the SLC12A3 gene.33Vargas-Poussou R. Dahan K. Kahila D. et al.Spectrum of mutations in Gitelman syndrome.J Am Soc Nephrol. 2011; 22: 693-703Crossref PubMed Scopus (155) Google Scholar The use of next-generation sequencing including genes involved in both Bartter and Gitelman syndromes is recommended to distinguish overlapping clinical phenotypes.32Blanchard A. Bockenhauer D. Bolignano D. et al.Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 24-33Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar The GWAS SNP that has the widest range of evidence supporting a causal role in hypertension through Na+ pathways is the uromodulin locus.34Padmanabhan S. Melander O. Johnson T. et al.Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.PLoS Genet. 2010; 6e1001177Crossref PubMed Scopus (295) Google Scholar Uromodulin is a protein produced exclusively by the TAL and distal convoluted tubule.35Devuyst O. Dahan K. Pirson Y. Tamm-Horsfall protein or uromodulin: new ideas about an old molecule.Nephrol Dial Transplant. 2005; 20: 1290-1294Crossref PubMed Scopus (84) Google Scholar Evidence from the last decade indicates its role in a novel hypertension pathway. Carriers of the minor G allele of the UMOD promoter SNP rs13333226 have lower levels of urinary uromodulin excretion and a lower risk of hypertension.34Padmanabhan S. Melander O. Johnson T. et al.Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.PLoS Genet. 2010; 6e1001177Crossref PubMed Scopus (295) Google Scholar,36Graham L.A. Padmanabhan S. Fraser N.J. et al.Validation of uromodulin as a candidate gene for human essential hypertension.Hypertension. 2014; 63: 551-558Crossref PubMed Scopus (90) Google Scholar This lower risk of hypertension is the result of resistance to sodium-induced elevations in BP, which has been demonstrated using UMOD knockout mice, which show a leftward shift in the pressure-natriuresis curve in response to saline loading.36Graham L.A. Padmanabhan S. Fraser N.J. et al.Validation of uromodulin as a candidate gene for human essential hypertension.Hypertension. 2014; 63: 551-558Crossref PubMe